Career Development: The objective of this K-23 Career Development Award application is to prepare the candidate for a career as an independent patient oriented researcher. The applicant's primary area of interest is in attenuating the adverse metabolic effects associated with antihypertensive therapy in patients with metabolic syndrome by identifying pharmacologic and pharmacogenomic combinations that maximize insulin sensitivity. The University of Florida has the resources to provide the applicant with the ideal setting to examine both the clinical and pharmacogenomic aspects of insulin resistance in the setting of antihypertensive therapy. The proposed career development plan incorporates a structured didactic program focused in epidemiology, which will result in a master's degree in epidemiology via the K30 program. Additionally, the applicant will participate in seminars, conferences and focused laboratory based research tutorials conducted by experts in the field of pharmacogenomics, epidemiology and glucose homeostasis in the setting of metabolic syndrome. Clinical and Laboratory Investigations. Patients with metabolic syndrome, characterized primarily by insulin resistance are at increased risk of developing diabetes and often have hypertension (HTN). Thiazide diuretics are recommended for treating HTN in patients with metabolic syndrome, despite being associated with metabolic disturbances that result in increased insulin resistance. The major hypothesis of this study is that in patients with metabolic syndrome and HTN, blockade of the renin-angiotensin system (RAS) with an angiotensin converting enzyme (ACE) inhibitor attenuates the adverse metabolic effects of a thiazide diuretic. Specific aims are designed to investigate whether this attenuation occurs after the addition of ACE inhibitor to diuretic and/or as a consequence of pretreatment with an ACE inhibitor. Also, laboratory based pharmacogenomic investigations will be conducted in a separate cohort of 6000 hypertensive CAD patients to identify polymorphisms associated with diabetes in the ACE, ADD1 and KCNJ1 genes, selected on the basis of their critical role in ACE inhibitor and diuretic response. This research seeks to overcome gaps in knowledge regarding the metabolic impact of antihypertensive drugs in patients with metabolic syndrome and will provide data to influence future prescribing patterns.